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Control of Pseudomonas aeruginosa in the Lung Requires the Recognition of Either Lipopolysaccharide or Flagellin¹

Reuben Ramphal^*,,, Viviane Balloy^*,, Jeevan Jyot, Amrisha Verma, Mustapha Si-Tahar^*, and Michel Chignard^2,*,

^* Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité 874, Paris, France; and Department of Medicine, University of Florida, Gainesville, FL 32611

Acute lung infection due to Pseudomonas aeruginosa is an increasingly serious problem that results in high mortality especially in the compromised host. In this study, we set out to ascertain what components of the TLR system are most important for innate immunity to this microorganism. We previously demonstrated that TLR2,4^–/– mice were not hypersusceptible to infection by a wild-type P. aeruginosa strain. However, we now find that mice lacking both TLR2 and TLR4 (TLR2,4^–/– mice) are hypersusceptible to infection following challenge with a P. aeruginosa mutant devoid of flagellin production. We demonstrate that this hypersusceptibilty is largely due to a lack of innate defense by the host that fails to control bacterial replication in the lung. Further evidence that a response to flagellin is a key factor in the failure of TLR2,4^–/– mice to control the infection with the mutant strain was obtained by demonstrating that the intrapulmonary administration of flagellin over a 18 h period following infection, saved 100% of TLR2,4^–/– mice from death. We conclude that the interactions of either TLR4 with LPS or TLR5 with flagellin can effectively defend the lung from P. aeruginosa infection and the absence of a response by both results in hypersusceptibility to this infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant AI 45014 from National Institutes of Health (to R.R.).

² Address correspondence and reprint requests to Dr. Michel Chignard, Institut Pasteur, 25 rue du Dr. Ro, 75015 Paris, France. E-mail address: chignard{at}pasteur.fr

³ Abbreviations used in this paper: PAMP, pathogen-associated molecular pattern; BAL, bronchoalveolar lavage; PMN, polymorphonuclear neutrophil.